Congenital Herpes Simplex Virus Infection Ashley S. Ross, M.D. Neonatology Fellow University of Arkansas for Medical Sciences Arkansas Children’s Hospital

Objectives 1. Recognize the clinical presentation of congenital (neonatal) herpes simplex virus (HSV) infection 2. Discuss current treatment modalities for neonatal herpes infection 3. Discuss long term sequelae of neonatal herpes infection

Transmission to the Neonate 1. Intrauterine 2. Intra-partum 3. Post-partum 5% of cases Ascending infection cervix or vulva Transplacental First 20 weeks Spontaneous abortion Stillbirth Congenital malformations Hydranencephaly Chorioretinitis Controversial

Transmission to the Neonate 1. Intrauterine 2. Intra-partum 3. Post-partum Represents 85% of cases Infected maternal secretions in birth canal Lesions at delivery, C- section preferred route of delivery

Transmission to the Neonate 1. Intrauterine 2. Intra-partum 3. Post-partum 10% of all cases of neonatal herpes Environmental sources Oral lesions Herpetic whitlow Other sites, such as breast

Neonatal HSV In USA, incidence 1 per 3,000 to 20,000 live births In USA, incidence 1 per 3,000 to 20,000 live births HSV-2 poorer prognosis HSV-2 poorer prognosis 75% of neonatal herpes 75% of neonatal herpes HSV-1 infection more common in Japan HSV-1 infection more common in Japan Incubation 2-14 days Incubation 2-14 days

Transmission of HSV to the Neonate Primary infection, symptomatic vs. asymptomatic reactivation Delivered vaginally, with primary infection 33%-50% risk of transmission Reactivation risk of transmission 0-5% Primary vs. recurrent often impossible to distinguish >75% of infants with HSV born w/o maternal symptoms Quantity and quality of maternal antibodies Duration of ruptured membranes (>4-6 hours) Use of fetal scalp monitor during labor

Clinical Manifestations 1. Disseminated disease 2. Localized central nervous system 3. Skin, eyes, and mouth (SEM) Presentation birth to 4 weeks Divided equally Overlap between groups Skin lesions not always present Makes diagnosis difficult May appear late in disseminated disease

Disseminated Disease Presentation earliest Presentation earliest 1 st week 1 st week 25% of neonatal cases 25% of neonatal cases Sepsis syndrome with negative bacterial cultures Sepsis syndrome with negative bacterial cultures Severe liver dysfunction Severe liver dysfunction Pneumonia Pneumonia Overlap with other types Overlap with other types

Disseminated Disease

Encephalitis in 75% of disseminated infections Encephalitis in 75% of disseminated infections Blood-borne route as opposed to neuronal spread Blood-borne route as opposed to neuronal spread MRI with panencephalitis possible MRI with panencephalitis possible High morbidity and mortality High morbidity and mortality 50% permanent neurological sequelae 50% permanent neurological sequelae 85% mortality if untreated 85% mortality if untreated If treated, 30% mortality If treated, 30% mortality Still 15% with permanent neurological impairment Still 15% with permanent neurological impairment

CNS Disease 35% of neonatal disease 35% of neonatal disease Presents later (2 nd to 3 rd week) Presents later (2 nd to 3 rd week) Seizures Seizures Lethargy Lethargy Tremors Tremors Poor feeding Poor feeding Temperature instability Temperature instability Mortality 50% when untreated 2/3 will have permanent neurological sequelae Temporal focus initially Focality on MRI or EEG Panencephalitis can develop

CNS Disease Coren ME, et al.J Neurol Neurosurg Psychiatry Aug;67(2):243-5.

CNS Disease Burke JW, et al. AJNR Am J Neuroradiol Apr;17(4):773-6.

CNS Disease CNS disease: CNS disease: HSV CSF culture rarely positive HSV CSF culture rarely positive Need HSV polymerase chain reaction (PCR) Need HSV polymerase chain reaction (PCR) Elevated CSF protein Elevated CSF protein Evidence of RBC’s Evidence of RBC’s Cutaneous lesion usually absent Cutaneous lesion usually absent

CNS Disease Predictors of poor outcome Predictors of poor outcome At time of treatment At time of treatment Comatose at initiation of therapy Comatose at initiation of therapy Premature Premature Seizures Seizures HSV-2 HSV-2 Persistently positive CSF HSV PCR Persistently positive CSF HSV PCR

SEM Disease 40% of neonatal HSV cases Presents at days of age 40% of neonatal HSV cases Presents at days of age Discrete vesicles and conjunctivitis Discrete vesicles and conjunctivitis Untreated disease Untreated disease 75% will progress to CNS or disseminated disease 75% will progress to CNS or disseminated disease 30-40% develop neurological impairment 30-40% develop neurological impairment Spastic quadriplegia, microcephaly, blindness Spastic quadriplegia, microcephaly, blindness Usually becomes apparent at 6-12 months Usually becomes apparent at 6-12 months Treat as aggressively as disseminate/CNS Treat as aggressively as disseminate/CNS

Diagnosis Average time from onset of symptoms to treatment is 6 days! Average time from onset of symptoms to treatment is 6 days! Time has not shortened Time has not shortened Early treatment, improved mortality/morbidity Early treatment, improved mortality/morbidity Absent skin lesions does NOT exclude diagnosis Absent skin lesions does NOT exclude diagnosis Absent maternal history does NOT exclude diagnosis Absent maternal history does NOT exclude diagnosis

Diagnosis Readily grows in cell culture Readily grows in cell culture Cytopathogenic effects seen in 1-3 days Cytopathogenic effects seen in 1-3 days Special media Special media For delayed inoculation For delayed inoculation Cultures negative at 15 days likely negative Cultures negative at 15 days likely negative Obtain cultures after 48 hours Obtain cultures after 48 hours

Diagnosis Viral cultures can be obtained from Viral cultures can be obtained from Unroofed lesions Unroofed lesions Urine Urine Nasopharynx or mouth Nasopharynx or mouth Rectum Rectum Blood Blood Readily grows in cell culture Readily grows in cell culture Cytopathogenic effects seen in 1-3 days Cytopathogenic effects seen in 1-3 days Special media Special media For delayed inoculation For delayed inoculation Cultures negative at 15 days likely negative Cultures negative at 15 days likely negative Obtain cultures after 48 hours Obtain cultures after 48 hours Surface contamination Surface contamination CSF for HSV PCR Attempt to seek evidence of disseminated disease with: Liver function tests CBC CSF analysis Chest x-ray IV acyclovir should be administered at time of lab evaluation Do not wait for lab results!!!!!

Diagnosis CSF cultures not useful (need PCR) CSF cultures not useful (need PCR) Serology not useful acutely Serology not useful acutely Direct fluorescent antibody (DFA) and Enzyme Immunoassay (ELISA) Direct fluorescent antibody (DFA) and Enzyme Immunoassay (ELISA) Typing of culture aspirates Typing of culture aspirates Supportive diagnosis Supportive diagnosis EEG EEG MRI MRI

Neonatal HSV: Treatment Treat all infections with IV acyclovir Treat all infections with IV acyclovir Acyclovir of 60 mg/kg/day IV divided Q8 hours Acyclovir of 60 mg/kg/day IV divided Q8 hours 14 days for SEM disease 14 days for SEM disease 21 days for disseminated or CNS disease 21 days for disseminated or CNS disease Repeat CSF analysis prior to end of therapy Repeat CSF analysis prior to end of therapy Consider tertiary referral, neonatologist/infectious disease referral Consider tertiary referral, neonatologist/infectious disease referral Monitor renal function and neutropenia Monitor renal function and neutropenia Keep well hydrated Keep well hydrated Twice weekly labs Twice weekly labs

Treatment Lumbar puncture at end of therapy for HSV PCR Lumbar puncture at end of therapy for HSV PCR Continue treatment until CSF sterile Continue treatment until CSF sterile Many will have recurrence Many will have recurrence May need long-term suppressive treatment May need long-term suppressive treatment May need intermittent acyclovir therapy May need intermittent acyclovir therapy Recurrent SEM under investigation Recurrent SEM under investigation Ocular involvement Ocular involvement Pediatric ophthalmologist Pediatric ophthalmologist Topical treatment with IV acyclovir Topical treatment with IV acyclovir

Treatment Maternal history of HSV without lesions Maternal history of HSV without lesions Observation of infant Observation of infant Appropriate evaluation is evidence of infection Appropriate evaluation is evidence of infection

Treatment Primary infection and exposed infant Primary infection and exposed infant At least 50% risk of infection At least 50% risk of infection Controversy over approach Controversy over approach Surface cultures hours after delivery Surface cultures hours after delivery Empiric therapy vs. treating only positive surface cultures Empiric therapy vs. treating only positive surface cultures Signs of infection/rash, immediate treatment and cultures Signs of infection/rash, immediate treatment and cultures Recurrent infection and exposed infant Surface cultures Observation Vesicular lesions Jaundice Respiratory distress Seizures Careful observation if cultures negative Treat positive cultures Any symptomatic infant is treated

Neonatal HSV: Prevention All mothers screened prenatally and at deliver All mothers screened prenatally and at deliver Delivery by C-section Delivery by C-section Clinically apparent lesions Clinically apparent lesions No invasive fetal monitoring No invasive fetal monitoring Risk of infection 50%-5% Risk of infection 50%-5% Within 4-6 hours of ROM Within 4-6 hours of ROM Maternal history of HSV without lesions Maternal history of HSV without lesions May deliver vaginally May deliver vaginally

Conclusion >75% of infants are born to mom’s without a history of lesions >75% of infants are born to mom’s without a history of lesions A lack of skin lesions does not eliminate the diagnosis of HSV A lack of skin lesions does not eliminate the diagnosis of HSV Think about HSV early and start therapy even if you only have a suspicion of HSV Think about HSV early and start therapy even if you only have a suspicion of HSV Remember your surface cultures Remember your surface cultures Remember liver function test Remember liver function test

References American Academy of Pediatrics. Herpes simplex. In: Pickering LK, ed Red Book: Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 2003:344–353 Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Frenkel LM, the NIAID Collaborative Antiviral Study Group. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics. 2001;108:223–229 Waggoner-Fountain LA, Grossman LB. Herpes Simplex Virus. Pediatrics in Review. 2004;25:86-93